DFT CALCULATIONS FOR VITAMIN B12 COMPOUNDS AND REACTIONS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 含有维生素B12的蛋氨酸合成酶是人体内最重要的酶之一，位于人体的重要代谢途径中。为了了解它们的化学和生化性质，需要对维生素B12化合物进行分子轨道计算，这种化合物称为钴胺，是钴-科林环系。我们用PM3半经验方法计算了甲钴胺的完整结构(183个原子，506个电子)，并用B3LYP/LANL2DZ方法对一个模型体系(73个原子，274个电子)进行了密度泛函理论计算。尽管PM3的几何构型与密度泛函理论的计算结果接近，但很明显，对于PM3的结果，能量和分子轨道轮廓甚至不是定性正确的。文献中以前的密度泛函模型计算都不是用带负电的磷酸盐侧链进行的，侧链会改变分子上的总电荷。我们以前的大多数DFT计算都是在单节点计算机上用Gauss(98或03)程序进行的，模型化合物的单个几何优化可能需要两周以上的时间(418个基函数，1097个原始高斯)。我们现在需要对更完整的模型钴胺体系进行密度泛函计算，这将需要多处理器计算和大量的内存，以便正确地模拟烷基钴胺、非钴胺、N2O-钴胺等物种的几何结构和键离解能，以及酶反应和化学反应中Co-C键和NO-Co键断裂的拉曼光谱、还原电位和过渡态。这些研究应该有助于理解甲硫氨酸合成酶活性部位的机制，该酶使用甲钴胺作为辅因子。计算将涉及准确的溶剂化计算，并最终涉及蛋氨酸合成酶的甲钴胺活性部位的QM/MM。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The vitamin B12 containing enzyme , methionine synthase, is one of the most important enzymes in the human body situated in essential metabolic pathways. Molecular orbital calculations on vitamin B12 compounds, called cobalamins , which are cobalt -corrin ring systems, are to be made to understand their chemical and biochemical properties. We have compared the PM3 semi-empirical method for the complete methylcobalamin structure ( 183 atoms, 506 electrons) with a DFT calculations at the B3LYP/LANL2DZ level for a model system of CH3-corrin Im (imidazole) (73 atoms, 274 electrons). Although PM3 geometry is close to that of the DFT calculations, it is clear that energies and molecular orbital contours are not even qualitatively correct for PM3 results. None of the previous DFT model calculations in the literature were made with the negatively charged phosphate containing side chain which would change the overall charge on the molecules. Most of our previous DFT calculations were made with the Gaussian ( 98 or 03) program on a single node computer and a single geometric optimization of the model compound could take more than two weeks ( 418 basis functions, 1097 primitive Gaussians). We now need to make DFT calculations on more complete model cobalamin systems which will require multiprocessor calculations and large amounts of memory , in order to correctly model geometry and bond dissociation energies of alkyl-cobalamins, NO-cobalamin, N2O-cobalamin , and other species, and Raman spectra, reduction potentials, and transition states in the enzymatic reactions and chemical reactions where the Co-C bond and NO-Co bonds are broken. These studies should help in understanding mechanisms at the active site of methionine synthase which uses methylcobalamin as a cofactor. Calculations will involve accurate solvation calculations and eventually QM/MM of the methylcobalamin active site of methionine synthase.